Bile-acid conjugates providing for sustained systemic concentration of drugs

ABSTRACT

This invention is directed to compounds that provide for sustained systemic concentrations of therapeutic or prophylactic agents following administration to animals. This invention is also directed to pharmaceutical compositions including and methods using such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application60/238,758, filed Oct. 6, 2000; 60/249,804, filed Nov. 17, 2000; and60/297,472, filed Jun. 11, 2001, all of which are incorporated byreference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to compounds that provide for sustainedsystemic concentrations of therapeutic or prophylactic agents followingadministration to animals. This invention is also directed topharmaceutical compositions including and methods using such compounds.

2. State of the Art

Rapid clearance of drugs from the systemic circulation represents amajor impediment to effective clinical use of therapeutic and/orprophylactic compounds. Although multiple factors can influence thesystemic concentrations of drugs achieved following administration(including drug solubility, dissolution rate, first-pass metabolism,p-glycoprotein and related efflux mechanisms, hepatic/renal elimination,etc), rapid systemic clearance is a particularly significant reason forsuboptimal systemic exposure to many compounds. Rapid systemic clearancemay require that large doses of drug be administered to achieve atherapeutic or prophylatic effect. Such larger doses of the drug,however, may result in greater variability in drug exposure, morefrequent occurrence of side effects, or decrease in patient compliance.Frequent drug administration may also be required to maintain systemicdrug levels above a minimum effective concentration. This problem isparticularly significant for drugs that must be maintained in a welldefined concentration window to provide continuous therapeutic orprophylactic benefit while minimizing adverse effects (including forexample, antibacterial agents, antiviral agents, anticancer agents,anticonvulsants, anticoagulants, etc.).

Conventional approaches to extend the systemic exposure of drugs withrapid clearance involve the use of formulation or device approaches thatprovide a slow or sustained release of drug within the intestinal lumen.These approaches are well known in the art and normally require that thedrug be well absorbed from the large intestine, where such formulationsare most likely to reside while releasing the drug. Drugs that areamenable to conventional sustained release approaches must be orallyabsorbed in the intestine and traverse this epithelial barrier bypassive diffusion across the apical and basolateral membranes of theintestinal epithelial cells. The physicochemical features of a moleculethat favor its passive uptake from the intestinal lumen into thesystemic circulation include low molecular weight (e.g. <500 Da),adequate solubility, and a balance of hydrophobic and hydrophiliccharacter (logP generally 1.5-4.0) (Navia and Chaturvedi, 1996).

Polar or hydrophilic compounds are typically poorly absorbed through ananimal's intestine as there is a substantial energetic penalty forpassage of such compounds across the lipid bilayers that constitutecellular membranes. Many nutrients that result from the digestion ofingested foodstuffs in animals, such as amino acids, di- andtripeptides, monosaccharides, nucleosides and water-soluble vitamins,are polar compounds whose uptake is essential to the viability of theanimal. For these substances there exist specific mechanisms for activetransport of the solute molecules across the apical membrane of theintestinal epithelia. This transport is frequently energized byco-transport of ions down a concentration gradient. Solute transporterproteins are generally single sub-unit, multi-transmembrane spanningpolypeptides, and upon binding of their substrates are believed toundergo conformational changes which result in movement of thesubstrate(s) across the membrane.

Over the past 10-15 years, it has been found that a number of orallyadministered drugs are recognized as substrates by some of thesetransporter proteins, and that this active transport may largely accountfor the oral absorption of these molecules (Tsuji and Tamai, 1996).While in most instances the transporter substrate properties of thesedrugs were unanticipated discoveries made through retrospectiveanalysis, it has been appreciated that, in principle, one might achievegood intestinal permeability for a drug by designing in recognition anduptake by a nutrient transport system. Drugs subject to activeabsorption in the small intestine are often unable to passively diffuseacross epithelial cell membranes and are too large to pass through thetight junctions that exist between the intestinal cells. These drugsinclude many compounds structurally related to amino acids, dipeptides,sugars, nucleosides, etc. (for example, many cephalosporins, ACEinhibitors, AZT, gabapentin, pregabalin, baclofen, etc.)

Numerous structural analogs of γ-aminobutyric acid (GABA) (1) andL-glutamic acid have been described in the art as pharmaceutical agents(U.S. Pat. No. 4,024,175, U.S. Pat. No. 5,563,175, U.S. Pat. No.6,020,370, U.S. Pat. No. 6,028,214, U.S. Pat. No. 6,103,932, U.S. Pat.No. 6,117,906, WO9209560, WO9323383, WO9729101, WO9733858, WO9733859,WO9817627, WO9908671, WO9921824, WO9931057, WO9931074, WO9931075,WO9961424, WO0015611, WO0023067, WO0031020, WO0050027). Examples includegabapentin (2), pregabalin (3), vigabatrin (4), and baclofen (5) (seeFIG. 1). Gabapentin was designed as a lipophilic GABA analog and waslaunched in 1994 as an anticonvulsant therapy for the treatment ofepilepsy. During human trials and while in clinical use, it becameapparent that gabapentin induced some other potentially usefultherapeutic effects in chronic pain states and behavioral disorders.Gabapentin currently finds significant off-label use in clinicalmanagement of neuropathic pain. Pregabalin has been shown to have asimilar pharmacological profile to gabapentin with greater potency inpreclinical models of pain and epilepsy and is presently in Phase IIIclinical trials. It has been demonstrated that gabapentin, pregabalin,and related structural analogs are absorbed specifically in the smallintestine by the large neutral amino acid transporter (LNAA) (Jezyk etal, 1999). Rapid systemic clearance of these compounds requires thatthey be dosed frequently to maintain a therapeutic or prophylacticconcentration in the systemic circulation (Bryans and Wustrow, 1999).Conventional sustained release approaches have not been successfullyapplied to these drugs as they are not absorbed from the largeintestine. Thus there is a significant need for effective sustainedrelease versions of these drugs, particularly for the pediatric patientpopulation, since drug must be administered during school hours, raisingthe issues of compliance, liability, and social acceptance.

One attractive pathway that might be exploitable for sustained deliveryof drugs with rapid systemic clearance such as GABA analogs is theentero-hepatic circulation of bile acids (Swaan et al, 1996). Bile acidsare hydroxylated steroids that play a key role in digestion andabsorption of fat and lipophilic vitamins. After synthesis in the liver,they are secreted into bile and excreted by the gall bladder into theintestinal lumen where they emulsify and help solubilize lipophilicsubstances. Bile acids are conserved in the body by active uptake fromthe terminal ileum via the sodium-dependent transporter IBAT (or ASBT)and subsequent hepatic extraction by the transporter NTCP (or LBAT)located in the sinusoidal membrane of hepatocytes. This efficientmechanism to preserve the bile acid pool is termed the enterohepaticcirculation (see FIG. 2). In man, the total bile acid pool (3-5 g)recirculates 6-10 times per day giving rise to a daily uptake ofapproximately 20-30 g of bile acids.

The high transport capacity of the bile acid pathway has been a keyreason for interest in this system for drug delivery purposes. Severalpapers have postulated that chemical conjugates of bile acids with drugscould be used to provide liver site-directed delivery of a drug to bringabout high therapeutic concentrations in the diseased liver withminimization of general toxic reactions elsewhere in the body; andgallbladder-site delivery systems of cholecystographic agents andcholesterol gallstone dissolution accelerators” (Ho, 1987). Severalgroups have explored these concepts in some detail, using the C-24carboxylic acid, C-3, C-7, and C-12 hydroxyl groups of cholic acid (andother bile acids) as handles for chemically conjugating drugs or drugsurrogates. (Kramer et al, 1992; Kim et al, 1993).

The most rigorous drug targeting studies using the bile acid transportpathway to date relate to work with bile acid conjugates of HMG-CoAreductase inhibitors (Kramer et al, 1994b; Petzinger et al, 1995; Kramerand Wess, 1995; Kramer et al, 1997b). Coupling of the HMG-CoA reductaseinhibitor HR 780 via an amide linkage to the C-3 position of cholate,taurocholate and glycocholate afforded substrates for both the ileal andliver bile acid transporter proteins (FIG. 3). Upon oral dosing of rats,the cholate conjugate S 3554 led to specific inhibition of HMG-CoAreductase in the liver, and in contrast to the parent compound HR 780,gave significantly reduced inhibition of the enzyme in extra-hepaticorgans. Companion studies that looked at the tissue distribution ofradiolabeled drugs two hours after i.v., administration through themesenteric vein of rats also showed dramatically lower systemic levelsfor the bile acid conjugate relative to the parent. Because inhibitionof HMG-CoA reductase requires the presence of the free carboxylic acidmoiety in HR 780 this data was taken to indicate that S 3554 served as aprodrug of HR 780, undergoing hydrolysis (and other uncharacterizedmetabolism) in the rat liver. Interestingly, uptake of S 3554 by liverdid not appear to depend on the liver bile acid transporter NTCP (whichprefers taurocholate conjugates), but may instead have involved anothermultispecific organic anion transport system on the sinusoidalhepatocyte membrane.

In summary, while the concept of harnessing the intestinal bile aciduptake pathway to enhance the absorption of poorly absorbed drugs iswell appreciated, the existing art has merely demonstrated that bileacid-drug conjugates may be effectively trafficked to the liver andgenerally excreted into the bile, either unchanged or as some type ofmetabolite. The art gives no guidance as to how one prepares acomposition that exploits the bile acid transport pathway andsimultaneously provides therapeutically meaningful levels of a drugsubstance outside of the enterohepatic circulation. Furthermore, the artdoes not describe the potential use of the bile acid transport pathwayto achieve a circulating reservoir of conjugated drug that is slowlyreleased into the systemic circulation to provide sustainedconcentrations.

SUMMARY OF THE INVENTION

This invention is directed to the surprising discovery that the bileacid transport system can be utilized to provide sustained systemicconcentrations of drugs administered to an animal. This invention,therefore, permits sustained therapeutic or prophylactic systemic bloodconcentrations of drugs which heretofore could not be achieved.

Accordingly, in one of its compound aspects, this invention is directedto compounds that provide for sustained therapeutic or prophylacticblood concentrations of a GABA analog drug or an active metabolitethereof in the systemic circulation of an animal. Such compounds are offormula (I):

wherein:

R¹ and R² are independently hydrogen or hydroxy;

X is selected from the group consisting of hydroxy and Q^(x)-G- where:

G is —O—, —C(O)O— or —NH—;

Q^(x) is a group derived from a linear oligopeptide comprising a firstmoiety D and further comprising from 1 to 3 amino acids, and whereinsaid group is cleavable from (I) under physiological conditions;

D is a GABA analog moiety;

Z is selected from the group consisting of:

(i) a substituted alkyl group containing a moiety which is negativelycharged at physiological pH, which moiety is selected from the groupconsisting of —COOH, —SO₃H, —SO₂H, —P(O)(OR¹⁶)(OH), —OP(O)(OR¹⁶)(OH),—OSO₃H and the like, and where R¹⁶ is selected from the group consistingof alkyl, substituted alkyl, aryl and substituted aryl; and (ii) a groupof the formula -M-Q^(x′), wherein M is selected from the groupconsisting of —CH₂OC(O)— and —CH₂CH₂C(O)—, and wherein Q^(x′) is a groupderived from a linear oligopeptide comprising a first moiety D′ andfurther comprising from 1 to 3 amino acids, and wherein said group iscleavable under physiological conditions;

D′ is a GABA analog moiety;

or a pharmaceutically acceptable salt thereof;

provided that when X is hydroxy, then Z is a group of formula -M-Q^(x′)and further provided that the compounds are transported across theintestinal wall.

Q^(x) and/or Q^(x′) may be transported by a transporter selected fromthe PEPT1 oligopeptide transporter and PEPT2 oligopeptide transporter.

Typically, where X is Q^(x)-G-, Q^(x) is of one of the following twostructures:—I_(i)-J_(j)-D-K_(k)—R⁴⁰or-T_(t)-D-U_(u)—V_(v)—R⁴¹

wherein

I is —[NR⁵⁰—(CR⁵¹R⁵²)_(a)—(CR⁵³R⁵⁴)_(b)—C(O)]—;

J is —[NR⁵⁵—(CR⁵⁶R⁵⁷)_(c)—(CR⁵⁸R⁵⁹)_(d)—C(O)]—;

K is —[NR⁶⁰—(CR⁶¹R⁶²)_(e)—(CR⁶³R⁶⁴)_(f)—C(O)]—;

T is —[C(O)—(CR⁶⁵R⁶⁶)_(g)—(CR⁶⁷R⁶⁸)_(h)—NR⁶⁹]—;

U is —[C(O)—(CR⁷⁰R⁷¹)_(m)—(CR⁷²R⁷³)_(n)—NR⁷⁴]—;

V is —[C(O)—(CR⁷⁵R⁷⁶)_(o)—(CR⁷⁷R⁷⁸)_(p)—NR⁷⁹]—;

R⁴⁰ is —OR¹⁷ or —OH;

R⁴¹ is H, —C(O)R¹⁷, —C(O)OR¹⁷;

R¹⁷ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

a, b, c, d, e, f, g, h, m, n, o and p are independently 0 or 1, whereinat least one of a and b is 1, at least one of c and d is 1, at least oneof e and f is 1, at least one of g and h is 1, at least one of m and nis 1, at least one of o and p is 1;

i, j, k, t, u and v are independently 0 or 1, wherein at least one of i,j and k is 1, and wherein at least one of t, u and v is 1;

R⁵⁰ is hydrogen or R⁵⁰ and R⁵¹ together with the atoms to which they areattached form a heterocyclyl ring;

R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵¹ andR⁵³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵⁵ is hydrogen or R⁵⁵ and R⁵⁶, together with the atoms to which theyare attached form a heterocyclyl ring;

R⁵⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵⁶ and R⁵⁷ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵⁶ andR⁵⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁵⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵⁸ and R⁵⁹ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁵⁹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶⁰ is hydrogen or R⁶⁰ and R⁶¹, together with the atoms to which theyare attached form a heterocyclyl ring;

R⁶¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶¹ and R⁶² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶¹ andR⁶³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁶² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶³ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶³ and R⁶⁴ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁶⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶⁵ and R⁶⁶ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶⁵ andR⁶⁷ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁶⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶⁷ and R⁶⁸ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁶⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁶⁹ is hydrogen or R⁶⁹ and R⁶⁸ together with the atoms to which they areattached form a heterocyclyl ring;

R⁷⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁷⁰ and R⁷¹ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁷⁰ andR⁷² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁷¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁷² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁷² and R⁷³ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁷³ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁷⁴ is hydrogen or R⁷⁴ and R⁷³ together with the atoms to which they areattached form a heterocyclyl ring;

R⁷⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁷⁵ and R⁷⁶ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁷⁵ andR⁷⁷ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁷⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁷⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁷⁷ and R⁷⁸ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁷⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; and

R⁷⁹ is hydrogen or R⁷⁹ and R⁷⁸ together with the atoms to which they areattached form a heterocyclyl ring.

Typically, where Z is a substituted alkyl group of the formula-M-Q^(x′), Q^(x′) is:—I′_(i′)-J′_(j′)-D′-K′_(k′)—R^(40′)

wherein

I′ is —[NR^(50′)—(CR^(51′)R^(52′))_(a′)—(CR^(53′)R^(54′))_(b′)—C(O)]—;

J′ is —[NR^(55′)—(CR^(56′)R^(57′))_(c′)—(CR^(58′)R^(59′))_(d′)—C(O)]—;

K′ is —[NR^(60′)—(CR^(61′)R^(62′))_(e′)—(CR^(63′)R^(64′))_(f′)—C(O)]—;

R^(40′) is OH or OR¹⁷;

a′, b′, c′, d′, e′ and f′ are independently 0 or 1;

i′, j′, and k′ are independently 0 or 1;

R^(50′) is hydrogen or R^(50′) and R^(51′) together with the atoms towhich they are attached form a heterocyclyl ring;

R^(50′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(51′) and R^(52′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R^(51′)and R^(53′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R^(52′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

R^(53′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(53′) and R^(54′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R^(54′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

R^(55′) is hydrogen or R^(55′) and R^(56′), together with the atoms towhich they are attached form a heterocyclyl ring;

R^(56′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(56′) and R^(57′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R^(56′)and R^(58′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R^(57′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

R^(58′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(58′) and R^(59′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R^(59′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

R^(60′) is hydrogen or R^(60′) and R^(61′), together with the atoms towhich they are attached form a heterocyclyl ring;

R^(61′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(61′) and R^(62′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R^(61′)and R^(63′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R^(62′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

R^(63′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R^(63′) and R^(64′) togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R^(64′) is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl.

Preferably, R¹ and R² of a compound of formula (I) are both α-OH; or R¹is β-OH and R² is hydrogen; or R¹ is α-OH and R² is hydrogen; or R¹ ishydrogen and R² is α-OH; or R¹ is β-OH and R² is α-OH; or R¹ and R² areboth hydrogen.

Preferably, substituent D is a compound of formula (I), which is a GABAanalog moiety, is of the following formula:

wherein

R³ is a covalent bond linking D to either J_(j) or U_(u);

R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms to which they areattached form a heterocyclic ring;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substitutedaryl, heteroaryl and substituted heteroaryl, or R⁷ and R⁸ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclic or substituted heterocyclic ring;

R⁹ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl;

R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

R¹¹ is —C(O)R¹²;

R¹² is a covalent bond linking D to either K_(k) or T_(t);

or a pharmaceutically acceptable salt thereof.

Preferably, substituent D′ of a compound of formula (I), which is a GABAanalog moiety, is of the following formula:

wherein

R^(3′) is a covalent bond linking D′ to J′_(j′);

R^(4′) is hydrogen, or R^(4′) and R^(9′) together with the atoms towhich they are attached form a heterocyclic ring;

R^(5′) and R^(6′) are independently selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

R^(7′) and R^(8′) are independently selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl,substituted aryl, heteroaryl and substituted heteroaryl, or R^(7′) andR^(8′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclic or substitutedheterocyclic ring;

R^(9′) is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

R^(10′) is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

R^(11′) is —C(O)R^(12′);

R^(12′) is a covalent bond linking D′ to K′_(k′);

or a pharmaceutically acceptable salt thereof.

When amino acids I, J, K, T, U and V are included in a compound offormula (I), they are typically derived from naturally occurring α-aminoacids.

When amino acids I′, J′ and K′ are included in a compound of formula(I), they are typically derived from naturally occurring α-amino acids.

Preferably, the GABA analog moiety D of formula (I) is selected from thegroup consisting of the following moieties:

Preferably, the GABA analog moiety D′ of formula (I) is selected fromthe group consisting of the following moieties:

Preferably, where Q^(x) of a compound of formula (I) is of the structure—I_(i)-J_(j)-D-K_(k)—R⁴⁰ or -T_(t)-D-U_(u)—V_(v)—R⁴¹, then b, c, d, e,f, g, h, j, k, m, n, o and p are 0, and a and i are 1.

Preferably, where Q^(x′) of a compound of formula (I) is of thestructure —I′_(i′)-J′_(j′)-D′-K′_(k′)—R^(40′), then b′, c′, d′, e′ andf′ are 0, and a′ is 1.

Preferably, with respect to substituents included in a compound offormula (I), X is hydroxy and Q^(x′) is—I′_(i′)-J′_(j′)-D′-K′_(k′)—R^(40′).

Preferably, the compound of formula (I) is selected from a groupconsisting of the following compounds:

Preferably in the method, where a compound of formula (I) contains thesubstituents R^(50′), R^(51′) and R^(52′), the substituents are definedas follows: R^(50′) is hydrogen, R^(51′) is selected from the groupconsisting of hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl,cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl,2-indolyl, —CH₂OH, —CH(OH)CH₃, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃ orCH₂SH, and R^(52′) is hydrogen.

In a method aspect of this invention, the compounds of this inventionare preferably used in a method for achieving sustained therapeutic orprophylactic blood concentrations of a GABA analog, or an activemetabolite thereof, in the systemic circulation of an animal. The methodinvolves administering a compound of formula (I) to an animal.

In a composition aspect of this invention, the compounds of thisinvention are mixed with a pharmaceutically acceptable carrier toprovide a composition. The composition is preferably used in the methodof achieving sustained therapeutic or prophylactic blood concentrationsof a GABA analog drug or an active metabolite thereof discussed above.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates structural analogs of γ-aminobutyric acid (GABA).

FIG. 2 illustrates the enterohepatic circulation with key transporterproteins identified which mediate bile acid circulation.

FIG. 3 illustrates HMG-CoA reductase inhibitor HR 780 as well asconjugates employing the lactone-opened ring of HR 780 coupled to a bileacid.

FIGS. 4-8 illustrate reaction sequences for preparation of variouscompounds of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to compounds that provide for sustainedsystemic concentrations of therapeutic or prophylactic GABA analogsfollowing administration to animals. This invention is also directed tomethods using the compounds and pharmaceutical compositions that areused in such methods. However, prior to describing this invention infurther detail, the following terms will first be defined:

Definitions

As used herein, the term “animal” refers to various species such asmammalian and avian species including, by way of example, humans,cattle, sheep, horses, dogs, cats, turkeys, chicken, and the like.Preferably, the animal is a mammal and even more preferably is a human.

“Administering to the animal” refers to delivering a compound of formula(I) to an animal through a suitable route. Such routes include, forexample, oral, rectal, subcutaneous, intravenous, intramuscular andintranasal. Preferably, the compound is orally administered to theanimal.

“Orally delivered drugs” refer to drugs which are administered to ananimal in an oral form, preferably, in a pharmaceutically acceptablediluent. Oral delivery includes ingestion of the drug as well as oralgavage of the drug.

“PEPT1 oligopeptide transporter” refers to a type of protein thatabsorbs peptides in certain tissues, such as the intestine. Thistransporter is described and characterized in the literature. See Adibi,S. A., Gastroenterology 1997, 113, 332-340 and Leibach et al., Ann. Rev.Nutr. 1996, 16, 99-119 for a discussion of the transporter.

“PEPT2 oligopeptide transporter” refers to a type of protein thatabsorbs peptides in certain tissues, such as the kidney. Thistransporter is described and characterized in the literature. See Dieck,S. T. et al., GLIA 1999, 25, 10-20, Leibach et al., Ann. Rev. Nutr.1996, 16, 99-119; and Wong et al., Am. J. Physiol. 1998, 275, C967-C975for a discussion of the transporter.

“Transported by either a PEPT1 or PEPT2 oligopeptide transporter” refersto the translocation of a molecule across a membrane of a cellexpressing the transporter. The translocation occurs through interactionwith the transporter and is energized by cotransport of H⁺ ions acrossthe membrane.

“Amino acid” is intended to denote α-amino acids and β-amino acids only.α-Amino acids are molecules of the formula HNR⁵⁰—CR⁵¹R⁵²—C(O)OH:wherein:

R⁵⁰ is hydrogen or R⁵⁰ and R⁵¹ together with the atoms to which they areattached form a heterocyclyl ring;

R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring.

β-Amino acids are molecules of formula:HNR⁵⁰—(CR⁵¹R⁵²)—(CR⁵³R⁵⁴)—C(O)OH:wherein:

R⁵⁰ is hydrogen or R⁵⁰ and R⁵¹ together with the atoms to which they areattached form a heterocyclyl ring;

R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵¹ andR⁵³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl.

“Naturally occurring amino acid” refers to any of the alpha-amino acidsthat are the chief components of proteins. The amino acids are eithersynthesized by living cells or are obtained as essential components ofthe diet. Such amino acids include, for example, the following: alanine,arginine, asparagines, aspartic acid, cysteine, glutamine, glutamicacid, glycine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, proline, serine, threonine, tryptophan, tyrosine andvaline.

“GABA analog” refers to a compound of one of the following formulae:

wherein:

R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms to which they areattached form a heterocyclic ring;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substitutedaryl, heteroaryl and substituted heteroaryl, or R⁷ and R⁸ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclic or substituted heterocyclic ring;

R⁹ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl;

R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

R¹¹ is selected from the group consisting of carboxylic acid, phosphonicacid, acidic heterocycle, sulfonic acid and hydroxamic acid;

R^(4′) is hydrogen, or R^(4′) and R^(9′) together with the atoms towhich they are attached form a heterocyclic ring;

R^(5′) and R^(6′) are independently selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

R^(7′) and R^(8′) are independently selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl,substituted aryl, heteroaryl and substituted heteroaryl, or R^(7′) andR^(8′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclic or substitutedheterocyclic ring;

R^(9′) is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

R^(10′) is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

R^(11′) is selected from the group consisting of carboxylic acid,carboxylic amide, carboxylic ester, sulfonamide, phosphonic acid, acidicheterocycle, sulfonic acid and hydroxamic acid.

“Acidic heterocycle” refers to a reprotonatable heterocycle having a pKaless than 7.0. Examples of such heterocycles include the following:

“Linear oligopeptide” refers to an amide oligomer comprising either aterminal amino group or a terminal carboxylic acid group or (preferably)both a terminal amino group and a terminal carboxylic acid group, whicholigomer is formed by condensation of the terminal amino residue of atleast one amino acid (or GABA analog) with the terminal carboxylic acidresidue of at least a second amino acid (or GABA analog). In addition tothe GABA analog, the amino acids comprising the oligopeptide areoptionally either α-amino acids, β-amino acids, or a mixture of α-aminoacids and β-amino acids. Note that when an α-amino acid additionallycontains either a β-amino group or a β-carboxylic acid group (e.g. as inaspartic acid) a linear oligopeptide formed from such an amino acid isintended to imply that it is the α-amine or α-carboxylic acid moiety (orboth) of such residue that is involved in amide formation.

“Derived from a compound” refers to a moiety that is structurallyrelated to such a compound. The structure of the moiety is identical tothe compound except at 1 or 2 positions. At these positions either ahydrogen atom attached to a heteroatom, or a hydroxyl moiety of acarboxylic, phosphonic, phosphoric or sulfonic acid group has beenreplaced with a covalent bond that serves as a point of attachment toanother moiety. For example, the moiety:

is derived from a linear oligopeptide comprising glycine and the druggabapentin. In this moiety, a hydrogen atom has been replaced with acovalent bond. “Derived from a linear oligopeptide” is meant tospecifically denote that the point of attachment is either the terminalamino group or the terminal acid group of the oligopeptide.

The term “systemic bioavailability” refers to the rate and extent ofsystemic exposure to a drug or a metabolite thereof as reflected by thearea under the systemic blood concentration versus time curve.

“Translocation across the intestinal wall” refers to movement of a drugor drug conjugate by a passive or active mechanism, or both, across anepithelial cell membrane of any region of the gastrointestinal tract.

“Active metabolite of a drug” refers to products of in vivo modificationof the drug which have therapeutic or prophylactic effect.

“Therapeutic or prophylactic blood concentrations” refers to systemicexposure to a sufficient concentration of a drug or an active metabolitethereof over a sufficient period of time to effect disease therapy or toprevent the onset or reduce the severity of a disease in the treatedanimal.

“Sustained release” refers to release of a drug or an active metabolitethereof into the systemic circulation over a prolonged period of timerelative to that achieved by oral administration of a conventionalformulation of the drug.

“Tissue of the enterohepatic circulation” refers to the blood, plasma,intestinal contents, intestinal cells, liver cells, biliary tract or anyfraction, suspension, homogenate, extract or preparation thereof.

“Conjugating” refers to the formation of a covalent bond.

“Bile acid transport system” refers to any membrane transporter proteincapable of causing a bile acid or a derivative thereof to betranslocated across a membrane of a cell of the gastrointestinal tractor liver.

“Active transport or active transport mechanism” refers to the movementof molecules across cellular membranes that: a) is directly orindirectly dependent on an energy mediated process (i.e. driven by ATPhydrolysis, ion gradient, etc); or b) occurs by facilitated diffusionmediated by interaction with specific transporter proteins; or c) occursthrough a modulated solute channel.

“A moiety selected to permit a compound of formula (I) to betranslocated across the intestinal wall of an animal via the bile acidtransport system” refers to compounds which, when conjugated to the drug(directly or via a linker moiety), are translocated across theintestinal wall via the bile acid transport system. Evaluation of whichcandidate compounds can be so translocated across the intestinal wallcan be conducted by the in vitro assay set forth in Example 3 below.

“Treating” a particular disease or disorder means reducing the number ofsymptoms and/or severity of symptoms of the disease, and/or the furtherprogression of the disease or disorder is reduced or limited.“Preventing” a disease or disorder means preventing or inhibiting theonset or occurrence of the disease or disorder.

“Practical dosage regimen” refers to a schedule of drug administrationthat is practical for a patient to comply with. For human patients, apractical dosage regimen for an orally administered drug is likely to bean aggregate dose of less than 10 g/day.

“Amino-protecting group” or “amino-blocking group” refers to any groupwhich when bound to one or more amino groups prevents reactions fromoccurring at these amino groups and which protecting groups can beremoved by conventional chemical steps to reestablish the amino group.The particular removable blocking group is not critical and preferredamino blocking groups include, by way of example only, t-butyoxycarbonyl(t-BOC), benzyloxycarbonyl (CBZ), and the like.

“Carboxyl-protecting group” or “carboxyl-blocking group” refers to anygroup which when bound to one or more carboxyl groups prevents reactionsfrom occurring at these groups and which protecting groups can beremoved by conventional chemical steps to reestablish the carboxylgroup. The particular removable blocking group is not critical andpreferred carboxyl blocking groups include, by way of example only,esters of the formula —COOR″ where R″ is selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,aryl, substituted aryl, alkaryl, substituted alkaryl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic.

“Alkyl” refers to alkyl groups preferably having from 1 to 20 carbonatoms and more preferably 1 to 6 carbon atoms. This term is exemplifiedby groups such as methyl, t-butyl, n-heptyl, octyl, dodecyl and thelike.

“Substituted alkyl” refers to an alkyl group, preferably of from 1 to 20carbon atoms, having from 1 to 5 substituents selected from the groupconsisting of alkoxy, substituted alkoxy, acyl, acylamino,thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino,aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxylaryl,substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl,carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl,carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substitutedaryl, carboxylheteroaryl, carboxyl-substituted heteroaryl,carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic,cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substitutedheteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,mono- and di-heterocyclic amino, mono- and di-substituted heterocyclicamino, unsymmetric di-substituted amines having different substituentsselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic and substituted alkyl groups having aminogroups blocked by conventional blocking groups such as Boc, Cbz, formyl,and the like or alkyl/substituted alkyl groups substituted with—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substitutedalkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkoxy” refers to the group “alkyl-O-” which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

“Substituted alkoxy” refers to the group “substituted alkyl-O-”. “Acyl”refers to the groups H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—,alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substitutedalkynyl-C(O)— cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—,aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substitutedheteroaryl-C(O), heterocyclic-C(O)—, and substituted heterocyclic-C(O)—wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Acylamino” refers to the group —C(O)NRR where each R is independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic and whereeach R is joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Thiocarbonylamino” refers to the group —C(S)NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and where each R is joined to form, together with thenitrogen atom a heterocyclic or substituted heterocyclic ring whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—,alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substitutedalkynyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, cycloalkyl-C(O)O—,substituted cycloalkyl-C(O)O—, heteroaryl-C(O)O—, substitutedheteroaryl-C(O)O—, heterocyclic-C(O)O—, and substitutedheterocyclic-C(O)O— wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Alkenyl” refers to alkenyl group preferably having from 2 to 20 carbonatoms and more preferably 2 to 6 carbon atoms and having at least 1 andpreferably from 1-2 sites of alkenyl unsaturation.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkenyloxy” refers to the group —O-alkenyl.

“Substituted alkenyloxy” refers to the group —O-substituted alkenyloxy.

“Alkynyl” refers to alkynyl group preferably having from 2 to 20 carbonatoms and more preferably 3 to 6 carbon atoms and having at least 1 andpreferably from 1-2 sites of alkynyl unsaturation.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkylene” refers to a divalent alkylene group preferably having from 1to 20 carbon atoms and more preferably 1 to 6 carbon atoms. This term isexemplified by groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—),the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—) and the like.

“Substituted alkylene” refers to alkylene groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OS₂—NRR where R is hydrogen or alkyl,—NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkenylene” refers to a divalent alkenylene group preferably havingfrom 2 to 20 carbon atoms and more preferably 1 to 6 carbon atoms andhaving from 1 to 2 sites of alkenyl unsaturation. This term isexemplified by groups such as ethenylene (—CH═CH—), propenylene(—CH₂CH═CH—), and the like.

“Substituted alkenylene” refers to alkenylene groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkynylene” refers to a divalent alkynylene group preferably havingfrom 2 to 20 carbon atoms and more preferably 1 to 6 carbon atoms andhaving from 1 to 2 sites of alkynyl unsaturation. This term isexemplified by groups such as ethynylene, propynylene and the like.

“Substituted alkynylene” refers to alkynylene groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Amidino” refers to the group H₂NC(═NH)— and the term “alkylamidino”refers to compounds having 1 to 3 alkyl groups (e.g., alkylHNC(═NH)—).

“Thioarnidino” refers to the group RSC(═NH)— where R is hydrogen oralkyl.

“Aminoacyl” refers to the groups —NRC(O)alkyl, —NRC(O)substituted alkyl,—NRC(O)cycloalkyl, —NRC(O)substituted cycloalkyl, —NRC(O)alkenyl,—NRC(O)substituted alkenyl, —NRC(O)alkynyl, —NRC(O)substituted alkynyl,—NRC(O)aryl, —NRC(O)substituted aryl, —NRC(O)heteroaryl,—NRC(O)substituted heteroaryl, —NRC(O)heterocyclic, and—NRC(O)substituted heterocyclic where R is hydrogen or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminocarbonyloxy” refers to the groups —NRC(O)O-alkyl,—NRC(O)O-substituted alkyl, —NRC(O)O-alkenyl, —NRC(O)O-substitutedalkenyl, —NRC(O)O-alkynyl, —NRC(O)O-substituted alkynyl,—NRC(O)O-cycloalkyl, —NRC(O)O-substituted cycloalkyl, —NRC(O)O-aryl,—NRC(O)O-substituted aryl, —NRC(O)O-heteroaryl, —NRC(O)O-substitutedheteroaryl, —NRC(O)O-heterocyclic, and —NRC(O)O-substituted heterocyclicwhere R is hydrogen or alkyl and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Oxycarbonylamino” refers to the groups —OC(O)NH₂, —OC(O)NRR,—OC(O)NR-alkyl, —OC(O)NR-substituted alkyl, —OC(O)NR-alkenyl,—OC(O)NR-substituted alkenyl, —OC(O)NR-alkynyl, —OC(O)NR-substitutedalkynyl, —OC(O)NR-cycloalkyl, —OC(O)NR-substituted cycloalkyl,—OC(O)NR-aryl, —OC(O)NR-substituted aryl, —OC(O)NR-heteroaryl,—OC(O)NR-substituted heteroaryl, —OC(O)NR-heterocyclic, and—OC(O)NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form, together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Oxythiocarbonylamino” refers to the groups —OC(S)NH₂, —OC(S)NRR,—OC(S)NR-alkyl, —OC(S)NR-substituted alkyl, —OC(S)NR-alkenyl,—OC(S)NR-substituted alkenyl, —OC(S)NR-alkynyl, —OC(S)NR-substitutedalkynyl, —OC(S)NR-cycloalkyl, —OC(S)NR-substituted cycloalkyl,—OC(S)NR-aryl, —OC(S)NR-substituted aryl, —OC(S)NR-heteroaryl,—OC(S)NR-substituted heteroaryl, —OC(S)NR-heterocyclic, and—OC(S)NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminocarbonylamino” refers to the groups —NRC(O)NRR, —NRC(O)NR-alkyl,—NRC(O)NR-substituted alkyl, —NRC(O)NR-alkenyl, —NRC(O)NR-substitutedalkenyl, —NRC(O)NR-alkynyl, —NRC(O)NR-substituted alkynyl,—NRC(O)NR-aryl, —NRC(O)NR-substituted aryl, —NRC(O)NR-cycloalkyl,—NRC(O)NR-substituted cycloalkyl, —NRC(O)NR-heteroaryl, and—NRC(O)NR-substituted heteroaryl, —NRC(O)NR-heterocyclic, and—NRC(O)NR-substituted heterocyclic where each R is independentlyhydrogen, alkyl or where each R is joined to form together with thenitrogen atom a heterocyclic or substituted heterocyclic ring as well aswhere one of the amino groups is blocked by conventional blocking groupssuch as Boc, Cbz, formyl, and the like and wherein alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aminothiocarbonylamino” refers to the groups —NRC(S)NRR,—NRC(S)NR-alkyl, —NRC(S)NR-substituted alkyl, —NRC(S)NR-alkenyl,—NRC(S)NR-substituted alkenyl, —NRC(S)NR-alkynyl, —NRC(S)NR-substitutedalkynyl, —NRC(S)NR-aryl, —NRC(S)NR-substituted aryl,—NRC(S)NR-cycloalkyl, —NRC(S)NR-substituted cycloalkyl,—NRC(S)NR-heteroaryl, and —NRC(S)NR-substituted heteroaryl,—NRC(S)NR-heterocyclic, and —NRC(S)NR-substituted heterocyclic whereeach R is independently hydrogen, alkyl or where each R is joined toform together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring as well as where one of the amino groups is blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aryl” or “Ar” refers to a monovalent unsaturated aromatic carbocyclicgroup of from 6 to 14 carbon atoms having a single ring (e.g., phenyl)or multiple condensed rings (e.g., naphthyl or anthryl) which condensedrings may or may not be aromatic (e.g., 2-benzoxazolinone,2H-1,4-benzoxazin-3(4H)-one-7yl, and the like). Preferred aryls includephenyl and naphthyl.

“Substituted aryl” refers to aryl groups which are substituted with from1 to 3 substituents selected from the group consisting of hydroxy, acyl,acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl,aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl,substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substitutedcycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,substituted heterocyclyloxy, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheterocyclic, substituted thioheterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo,nitro, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substitutedalkyl, —S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

“Arylene” refers to a divalent unsaturated aromatic carbocyclic group offrom 6 to 14 carbon atoms having a single ring (e.g., phenylene) ormultiple condensed rings (e.g., naphthylene or anthrylene) whichcondensed rings may or may not be aromatic. Preferred arylenes includephenylene and naphthylene. Substituted arylene refers to arylene groupswhich are substituted with from 1 to 3 substituents selected from thegroup consisting of hydroxy, acyl, acylamino, thiocarbonylamino,acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

“Aryloxy” refers to the group aryl-O— which includes, by way of example,phenoxy, naphthoxy, and the like.

“Substituted aryloxy” refers to substituted aryl-O— groups.

“Aryloxyaryl” refers to the group -aryl-O-aryl.

“Substituted aryloxyaryl” refers to aryloxyaryl groups substituted withfrom 1 to 3 substituents on either or both aryl rings selected from thegroup consisting of hydroxy, acyl, acylamino, thiocarbonylamino,acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 8 carbon atomshaving a single cyclic ring including, by way of example, cyclopropyl,cyclobutyl, cyclopentyl, cyclooctyl and the like. Excluded from thisdefinition are multi-ring alkyl groups such as adamantanyl, etc.

“Cycloalkyloxy” refers to β-cycloalkyl.

“Cycloalkenyl” refers to cyclic alkenyl groups of from 3 to 8 carbonatoms having a single cyclic ring.

“Cycloalkenyloxy” refers to —O-cycloalkenyl.

“Substituted cycloalkyl” and “substituted cycloalkenyl” refers to ancycloalkyl or cycloalkenyl group, preferably of from 3 to 8 carbonatoms, having from 1 to 5 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,mono- and di-heterocyclic amino, mono- and di-substituted heterocyclicamino, unsymmetric di-substituted amines having different substituentsselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic and substituted alkynyl groups having aminogroups blocked by conventional blocking groups such as Boc, Cbz, formyl,and the like or alkynyl/substituted alkynyl groups substituted with—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substitutedalkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Substituted cycloalkyloxy” and “substituted cycloalkenyloxy” refers to—O-substituted cycloalkyl and —O-substituted cycloalkenyloxyrespectively.

“Cycloalkylene” refers to divalent cyclic alkylene groups of from 3 to 8carbon atoms having a single cyclic ring including, by way of example,cyclopropylene, cyclobutylene, cyclopentylene, cyclooctylene and thelike.

“Cycloalkenylene” refers to a divalent cyclic alkenylene groups of form3 to 8 carbon atoms having a single cyclic ring.

“Substituted cycloalkylene” and “substituted cycloalkenylene” refers toa cycloalkylene or cycloalkenylene group, preferably of from 3 to 8carbon atoms, having from 1 to 5 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂— substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,mono- and di-heterocyclic amino, mono- and di-substituted heterocyclicamino, unsymmetric di-substituted amines having different substituentsselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic and substituted alkynyl groups having aminogroups blocked by conventional blocking groups such as Boc, Cbz, formyl,and the like or alkynyl/substituted alkynyl groups substituted with—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substitutedalkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Cycloalkoxy” refers to —O-cycloalkyl groups.

“Substituted cycloalkoxy” refers to —O-substituted cycloalkyl groups.

“Guanidino” refers to the groups —NRC(═NR)NRR, —NRC(═NR)NR-alkyl,—NRC(═NR)NR-substituted alkyl, —NRC(═NR)NR-alkenyl,—NRC(═NR)NR-substituted alkenyl, —NRC(═NR)NR-alkynyl,—NRC(═NR)NR-substituted alkynyl, —NRC(═NR)NR-aryl,—NRC(═NR)NR-substituted aryl, —NRC(═NR)NR-cycloalkyl,—NRC(═NR)NR-heteroaryl, —NRC(═NR)NR-substituted heteroaryl,—NRC(═NR)NR-heterocyclic, and —NRC(═NR)NR-substituted heterocyclic whereeach R is independently hydrogen and alkyl as well as where one of theamino groups is blocked by conventional blocking groups such as Boc,Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“N,N-Dimethylcarbamyloxy” refers to the group —OC(O)N(CH₃)₂.

“Guanidinosulfone” refers to the groups —NRC(═NR)NRSO₂-alkyl,—NRC(═NR)NRSO₂-substituted alkyl, —NRC(═NR)NRSO₂-alkenyl,—NRC(═NR)NRSO₂-substituted alkenyl, —NRC(═NR)NRSO₂-alkynyl,—NRC(═NR)NRSO₂-substituted alkynyl, —NRC(═NR)NRSO₂-aryl,—NRC(═NR)NRSO₂-substituted aryl, —NRC(═NR)NRSO₂-cycloalkyl,—NRC(═NR)NRSO₂-substituted cycloalkyl, —NRC(═NR)NRSO₂-heteroaryl, and—NRC(═NR)NRSO₂-substituted heteroaryl, —NRC(═NR)NRSO₂-heterocyclic, and—NRC(═NR)NRSO₂-substituted heterocyclic where each R is independentlyhydrogen and alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is either chloro or bromo.

“Heteroaryl” refers to an aromatic carbocyclic group of from 2 to 10carbon atoms and 1 to 4 heteroatoms selected from the group consistingof oxygen, nitrogen and sulfur within the ring. Such heteroaryl groupscan have a single ring (e.g., pyridyl or furyl) or multiple condensedrings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls includepyridyl, pyrrolyl, indolyl and furyl.

“Substituted heteroaryl” refers to heteroaryl groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

“Heteroarylene” refers to a divalent aromatic carbocyclic group of from2 to 10 carbon atoms and 1 to 4 heteroatoms selected from the groupconsisting of oxygen, nitrogen and sulfur within the ring. Suchheteroarylene groups can have a single ring (e.g., pyridylene orfurylene) or multiple condensed rings (e.g., indolizinylene orbenzothienylene). Preferred heteroarylenes include pyridylene,pyrrolylene, indolylene and furylene.

“Substituted heteroarylene” refers to heteroarylene groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic, —OS(O)₂—substituted heterocyclic, —OSO₂—NRR where R is hydrogen or alkyl,—NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

“Heteroaryloxy” refers to the group —O-heteroaryl and “substitutedheteroaryloxy” refers to the group —O-substituted heteroaryl.

“Heterocycle,” “heterocyclic,” or “heterocyclyl” refers to a saturatedor unsaturated group having a single ring or multiple condensed rings,from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from thegroup consisting of nitrogen, sulfur or oxygen within the ring wherein,in fused ring systems, one or more the rings can be aryl or heteroaryl.

“Substituted heterocyclic” or “substituted heterocyclyl” refers toheterocycle groups which are substituted with from 1 to 3 substituentsselected from the group consisting of oxo (═O), thioxo (═S), alkoxy,substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino,amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,—C(O)O-aryl, —C(O)O-substituted aryl, heterocyclyloxy, substitutedheterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,mono- and di-heterocyclic amino, mono- and di-substituted heterocyclicamino, unsymmetric di-substituted amines having different substituentsselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic and substituted alkynyl groups having aminogroups blocked by conventional blocking groups such as Boc, Cbz, formyl,and the like or alkynyl/substituted alkynyl groups substituted with—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substitutedalkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

Examples of heterocycles and heteroaryls include, but are not limitedto, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, and thelike.

“Heterocyclene” refers to a divalent saturated or unsaturated grouphaving a single ring or multiple condensed rings, from 1 to 10 carbonatoms and from 1 to 4 hetero atoms selected from the group consisting ofnitrogen, sulfur or oxygen within the ring wherein, in fused ringsystems, one or more the rings can be aryl or heteroaryl.

“Substituted heterocyclene” refers to heterocyclene groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, —C(O)O-aryl, —C(O)O-substituted aryl,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Heterocyclyloxy” refers to the group —O-heterocyclic and “substitutedheterocyclyloxy” refers to the group —O-substituted heterocyclic.

“Thiol” refers to the group —SH.

“Thioalkyl” refers to the groups —S-alkyl

“Substituted thioalkyl” refers to the group —S-substituted alkyl.

“Thiocycloalkyl” refers to the groups —S-cycloalkyl.

“Substituted thiocycloalkyl” refers to the group —S-substitutedcycloalkyl.

“Thioaryl” refers to the group —S-aryl and “substituted thioaryl” refersto the group —S-substituted aryl.

“Thioheteroaryl” refers to the group —S-heteroaryl and “substitutedthioheteroaryl” refers to the group —S-substituted heteroaryl.

“Thioheterocyclic” refers to the group —S-heterocyclic and “substitutedthioheterocyclic” refers to the group —S-substituted heterocyclic.

“Amino” refers to the —NH₂ group.

“Substituted amino” refers to the —NR′R″ group wherein R′ and R″ areindependently hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic or where R′ and R″,together with the nitrogen atom pendent thereto, form a heterocyclicring.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound of Formulae (I), which salts are derived from avariety of organic and inorganic counter ions well known in the art andinclude, by way of example only, sodium, potassium, calcium, magnesium,ammonium, tetraalkylammonium, and the like; and when the moleculecontains a basic functionality, salts of organic or inorganic acids,such as hydrochloride, hydrobromide, tartrate, mesylate, acetate,maleate, oxalate and the like.

Utility

The compounds and methods described herein provide for the sustainedrelease of a GABA analog drug or active metabolite thereof relative todosing with the parent drug itself. In this regard, enterohepaticrecycling of the bile acid conjugates creates a reservoir for the activeagent.

For example, GABA analogs such as gabapentin and pregabalin are usefulin treating epilepsy, faintness attacks, hypokinesia, cranial disorders,neurodegnerative disorders, depression, anxiety, panic, pain,neuropathic pain, neuropatholgical disorders, gastrointestinal damage,inflammation and irritable bowel disease. See, for example, WO 99/31075which is incorporated herein by reference in its entirety.

General Synthetic Scheme

Compounds of this invention can be made by the methods depicted in thereaction schemes shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA),Emka-Chemie, or Sigma (St. Louis, Mo., USA) or are prepared by methodsknown to those skilled in the art following procedures set forth inreferences such as Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-15 (John Wiley and Sons, 1991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989), Organic Reactions, Volumes 140 (John Wiley and Sons, 1991),March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition),and Larock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989).

These schemes are merely illustrative of some methods by which thecompounds of this invention can be synthesized, and variousmodifications to these schemes can be made and will be suggested to oneskilled in the art having referred to this disclosure.

The starting materials and the intermediates of the reaction may beisolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography, and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Preparation of Compounds of Formula (I)

Schemes A and B describe alternative methods to prepare the compounds ofFormula (I).

Compounds of formula (I) where X, R¹ and R² are hydroxy, Z is asubstituted alkyl group containing a group of the formula -M-Q^(x′), Mis H₂CH₂C(O)—, Q^(x′) is of the structure -A^(x′)-D′ and A^(x′) isderived from an α-amino acid can be prepared as illustrated anddescribed in Scheme A below.

In reference to Scheme A, commercially available cholic acid (A) istreated with an activating agent, such as ethylchloroformate in thepresence of diisopropylethylamine, to provide an activated anhydride.The activated anhydride is reacted with amine (a) forming acid (B).Activation of (B) using an activating agent and condensation with amine(b) afford a compound of formula (I) as shown.

One of ordinary skill in the art will appreciate that cholic acid (A)could alternatively be reacted with amine (a) in the presence of acoupling agent (e.g., dicyclohexylcarbodiimide) to provide acid (B).Alternatively, cholic acid (A) could be coupled with the dipeptideresulting from first coupling amino acid (a) to compound (b).

A compound of formula (I) where R¹ and R² are hydroxy, Z is —CH₂CH₂CO₂H,X is Q^(x)-G-, G is —O—, Q^(x) is -D-A^(x) and A^(x) is derived from anα-amino acid can be prepared as illustrated and described in Scheme Bbelow.

In reference to Scheme B, compound (C), wherein R¹⁰⁰ is a carboxylprotecting group, is coupled with activated acid derivative (c), whereinR¹⁰¹ is a suitable leaving group (e.g., —OC(O)OEt). Selectivedeprotection of the amino protecting group (i.e., PG) provides compound(D). Activation of carboxylic acid (d) (e.g., treatment with ethylchloroformate in the presence of a tertiary amine) followed by additionof amine (D) then removal of protecting group R¹⁰⁰ yields the desiredcompound of formula (I).

One of ordinary skill in the art will appreciate that one could used acoupling agent to form the amide bonds above (i.e., bond between (C) and(c) or between (D) and (d)) rather than condensing an activated acidderivative (i.e., (c) or (d)) with an amine.

Additionally, FIGS. 4-8 and Examples 1-8 below describe in detail thesynthesis and biological activity of various bile acid-derivedcompounds, including other compounds of formula (I).

Pharmaceutical Formulations

When employed as pharmaceuticals, the compounds of formula (I) areusually administered in the form of pharmaceutical compositions. Thesecompounds can be administered by a variety of routes including oral,rectal, subcutaneous, intravenous, intramuscular and intranasal. Thesecompounds are effective as both injectable and oral compositions. Suchcompositions are prepared in a manner well known in the pharmaceuticalart and comprise at least one active compound.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of formula (I)above associated with pharmaceutically acceptable carriers. In makingthe compositions of this invention, the active ingredient is usuallymixed with an excipient, diluted by an excipient or enclosed within sucha carrier which can be in the form of a capsule, sachet, paper or othercontainer. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 0.1 to about 5000 mg, more usually about 10to about 2000 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other animals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It, willbe understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 mg to about 2 g of the activeingredient of the present invention.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solventsor mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be breathed directly from thenebulizing device or the nebulizing device may be attached to a facemasks tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention. Unless otherwise stated, alltemperatures are in degrees Celsius.

EXAMPLES

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

Atm=atmosphere

Boc=tert-butyloxycarbonyl

Cbz=carbobenzyloxy

CPM=counts per minute

DIC=diisopropylcarbodiimide

DMAP=4-N,N-dimethylaminopyridine

DMEM=Dulbecco's minimun eagle medium

DMF=N,N-dimethylformamide

DMSO=dimethylsulfoxide

FMOC=9-fluorenylmethyloxycarbonyl

g=gram

h=hour

HBSS=Hank's buffered saline solution

IBAT=intestinal bile acid transporter

L=liter

LBAT=liver bile acid transporter

LC/MS=liquid chromatography/mass spectroscopy

M=molar

min=minute

mL=milliliter

mmol=millimols

NTCP=Na+ taurocholate cotransporting polypeptide

PBS=phosphate buffered saline

PPTS=pyridinium p-toluenesulfonate

THF=tetrahydrofuran

TFA=trifluoroacetic acid

TMSOTf=trimethylsilyltrifluoromethanesulfonate

Trisyl=2,4,6-triispropylbenzenesulfonyl

μL=microliter

μM=micromolar

v/v=volume to volume

Experimental Methods

The following examples illustrate how the synthesis of GABA analogconjugates could be conducted in order to prepare compounds of formula(I). The syntheses described below are illustrated in FIG. 4-8.

Example 1 Synthesis of Cholic Acid Gabapentin Dipeptides (9)

Cholic acid (6) (408 mg, 1 mmol) was dissolved in anhydrous THF (10 mL)and triethylamine (0.167 mL, 1.2 mmol) added slowly with stirring. Thesolution was cooled to −5° C. in an ice-salt bath, and ethylchloroformate (0.12 mL, 1.2 mmol) added slowly, maintaining thetemperature between −5 to 0° C. After addition was complete, the coldmixture was stirred for an additional 15 minutes. A solution containingan amino acid (7) (1.75 mmol) in 2N NaOH (2 mL) was added and themixture stirred for an additional 60 min at −5 to 0° C. After removal ofthe THF in vacuo, saturated NaHCO₃ (15 mL) was added and the aqueousmixture washed with EtOAc (3×10 mL), then the pH adjusted to 3-4 withcitric acid. The product was extracted into EtOAc (3×15 mL), and thecombined organic phase dried over MgSO₄, and concentrated to dryness.The residue was purified by flash chromatography on silica gel (5%MeOH/CH₂Cl) to give the pure cholic acid adduct (8). This compound (0.4mmol) was dissolved in anhydrous ThF (10 mL) and triethylamine (0.44mmol) added slowly with stirring. The solution was cooled to −5° C. inan ice-salt bath, and ethyl chloroformate (44 μL, 0.44 mmol) addedslowly, maintaining the temperature between −5 to 0° C. After additionwas complete, the cold mixture was stirred for an additional 15 minutes.A solution containing gabapentin (2) (166 mg, 0.8 mmol) in 2N NaOH (3mL) was added and the mixture stirred for an additional 60 min at −5 to0° C. After removal of the THF in vacuo, saturated NaHCO₃ (10 mL) wasadded and the aqueous mixture washed with EtOAc (3×10 mL), then the pHadjusted to 34 with citric acid. The product was extracted into EtOAc(3×20 mL), and the combined organic phases dried over MgSO₄, andconcentrated to dryness. The residue was purified by flashchromatography on silica gel (10% MeOH/CH₂Cl₂) to give the pure cholicacid gabapentin dipeptide derivative. The corresponding sodium salt (9)was prepared in quantitative yield by addition of a methanol solution ofthe acid to water containing 0.5N NaOH (1 eq.) and evaporation todryness on a lyophilizer. Compounds were characterized by electrospraymass spectrometry as reported below:

Cholyl-Gly-Gabapentin (9a): MS (ESI): m/z 617.50 (M−H⁻), 619.51 (M+H⁺).¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 3.81 (s, 2H),3.34 (s, 2H), 2.28 (s, 2H), 1.03 (d, 3H, J=6.4 Hz), 0.91 (s, 3H), 0.70(s, 3H).

Cholyl-Ala-Gabapentin (9b): MS (ESI): m/z 631.50 (M−H⁻), 633.52 (M+H⁺).¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.29 (m, 1H),3.34 (s, 2H), 2.28 (s, 2H), 1.34 (d, 2H, J=6.8 Hz), 1.01 (d, 3H, J=6.4Hz), 0.91 (s, 3H), 0.71 (s, 3H).

Cholyl-Val-Gabapentin (9c): MS (ESI): m/z 659.55 (M−H⁻), 661.55 (M+H⁺).¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.26 (m, 1H),3.34 (s, 2H), 2.27 (s, 2H), 1.02 (d, 3H, J=6.4 Hz), 0.97 (d, 6H, J=6.4Hz), 0.91 (s, 3H), 0.71 (s, 3H).

Cholyl-Leu-Gabapentin (9d): MS (ESI): m/z 673.43 (M−H⁻), 675.45 (M+H⁺).¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.34 (m, 1H),3.34 (s, 2H), 2.27 (s, 2H), 1.02 (d, 3H, J=6.4 Hz), 0.97 (d, 3H, J=6.4Hz), 0.92 (d, 3H, J=6.4 Hz), 0.91 (s, 3H), 0.70 (s, 3H).

Cholyl-Norleu-Gabapentin (9e): MS (ESI): m/z 659.56 (M−H⁻), 661.57(M+H⁺). ¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.26(m, 1H), 3.34 (s, 2H), 2.27 (s, 2H), 1.02 (d, 3H, J=6.4 Hz), 0.91 (s,3H), 0.71 (s, 3H).

Cholyl-^(t)BuGly-Gabapentin (9f): MS (ESI): m/z 673.58 (M−H⁻), 675.58(M+H⁺). ¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.20(s, 1H), 3.34 (s, 2H), 2.29 (s, 2H), 1.01 (d, 3H, J=6.4 Hz), 0.98 (s,9H), 0.91 (s, 3H), 0.70 (s, 3H).

Cholyl-Phe-Gabapentin (9g): MS (ESI): m/z 707.47 (M−H⁻), 709.36 (M+H⁺).¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 7.26 (m, 5H),4.59 (m, 1H), 3.34 (s, 2H), 3.25-2.95 (m, 2H), 2.18 (d, 2H, J=7.2 Hz),0.98 (d, 3H, J=6.4 Hz), 0.91 (s, 3H), 0.68 (s, 3H).

Cholyl-Tyr-Gabapentin (9h): MS (ESI): m/z 723.42 (M−H⁻), 725.42 (M+H⁺).¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 7.06 (d, 2H,J=8.8 Hz), 6.69 (d, 2H, J=8.8 Hz), 4.51 (dd, 1H, J=6.8 Hz, J=8.8 Hz),3.34 (s, 2H), 3.16-2.78 (m, 2H), 2.16 (d, 2H, J=7.2 Hz), 0.98 (d, 3H,J=6.4 Hz), 091 (s, 3H), 0.68 (s, 3H).

Cholyl-Ser-Gabapentin (9i): MS (ESI): m/z 647.42 (M−H⁻), 649.41 (M+H⁺).¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.37 (m, 1H),3.78 (m, 2H), 3.34 (s, 2H), 2.15 (s, 2H), 1.03 (d, 3H, J=6.4 Hz), 0.91(s, 3H), 0.71 (s, 3H).

Cholyl-Asp-Gabapentin (9j): MS (ESI): m/z 647.45 (M−H⁻), 649.45 (M+H⁺).¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.71 (m, 1H),3.34 (s, 2H), 2.87-2.65 (m, 2H), 2.28 (s, 2H), 1.02 (d, 3H, J=6.4 Hz),0.91 (s, 3H), 0.71 (s, 3H).

Cholyl-Glu-Gabapentin (9k): MS (ESI): m/z 688.50 (M−H⁻), 690.54 (M+H⁺).¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.35 (m, 1H),3.34 (s, 2H), 2.38 (t, 2H, J=7 Hz), 1.02 (d, 3H, J=6.4 Hz), 0.91 (s,3H), 0.71 (s, 3H).

Cholyl-Asn-Gabapentin (9l): MS (ESI): m/z 674.43 (M−H⁻), 676.44 (M+H⁺).¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.29 (m, 1H),3.34 (s, 2H), 2.92-2.69 (m, 2H), 2.28 (s, 2H), 1.02 (d, 3H, J=6.4 Hz),0.91 (s, 3H), 0.70 (s, 3H).

Cholyl-Lys-Gabapentin (9m): MS (ESI): m/z 688.50 (M−H⁻), 690.54 (M+H⁺).¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.29 (m, 1H),3.34 (s, 2H), 2.28 (s, 2H), 1.02 (d, 3H, J=6.4 Hz), 0.91 (s, 3H), 0.70(s, 3H).

Cholyl-β-Ala-Gabapentin (9n): MS (ESI): m/z 631.45 (M−H⁻), 633.45(M+H⁺). ¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 3.34(s, 2H), 3.20 (t, 2H, J=8 Hz), 2.29 (s, 2H), 2.26 (t, 2H, J=8 Hz), 1.02(d, 3H, J=6.4 Hz), 0.91 (s, 3H), 0.70 (s, 3H).

Cholyl-Gaba-Gabapentin (9o): MS (ESI): m/z 645.56 (M−H⁻), 647.57 (M+H⁺).¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 3.34 (s, 2H),3.41 (t, 2H, J=6.8 Hz), 2.44 (t, 2H, J=6.8 Hz), 2.28 (s, 2H), 1.01 (d,3H, J=6.4 Hz), 0.91 (s, 3H), 0.71 (s, 3H).

Ursodeoxycbolyl-Phe-Gabapentin (9p): MS (ESI) m/z 691.6 (M−H⁻), 693.5(M+H⁺). ¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 7.26(m, 5H), 4.60 (m, 1H), 3.34 (s, 2H), 3.25-2.95 (m, 2H), 2.08 (d, 2H, J=7Hz), 0.95 (s, 3H), 0.91 (d, 3H, J=6.4 Hz), 0.67 (s, 3H).

Alternative Synthesis of Cholic Acid Gabapentin Dipeptides (9)

An N-Fmoc-protected amino acid (10) (1 mmol) is dissolved in anhydrousTHF (10 mL) and triethylamine (0.167 mL, 1.2 mmol) added slowly withstirring. The solution is cooled to −5° C. in an ice-salt bath, andethyl chloroformate (0.12 mL, 1.2 mmol) added slowly, maintaining thetemperature between −5 to 0° C. After addition is complete, the coldmixture is stirred for an additional 15 minutes. A solution containinggabapentin (2) (1.75 mmol) in 2N NaOH (2 mL) is added and the mixturestirred for an additional 60 min at −5 to 0° C. After removal of the THFin vacuo, saturated NaHCO₃ (15 mL) is added and the aqueous mixturewashed with EtOAc (3×10 mL), then the pH adjusted to 3-4 with citricacid. The product is extracted into EtOAc (3×15 mL), and the combinedorganic phase dried over MgSO₄, and concentrated to dryness. The residueis purified by flash chromatography on silica gel (5% MeOH/CH₂Cl₂) togive the pure protected dipeptide adduct. This compound is dissolved indry NMP (4 mL) containing 5% (v/v) DBU and the solution stirred for 30min to give the dipeptide (11). Cholic acid (6) (1 mmol) is dissolved inanhydrous THF (10 mL) and triethylamine (0.167 mL, 1.2 mmol) addedslowly with stirring. The solution is cooled to −5° C. in an ice-saltbath, and ethyl chloroformate (0.12 mL, 1.2 mmol) added slowly,maintaining the temperature between −5 to 0° C. After addition iscomplete, the cold mixture is stirred for an additional 15 minutes. Theabove solution of dipeptide (11) is added and the mixture stirred for anadditional 60 min at −5 to 0° C. After removal of the solvent in vacuo,saturated NaHCO₃ (15 mL) is added and the aqueous mixture washed withEtOAc (3×10 mL), then the pH adjusted to 3-4 with citric acid. Theproduct is extracted into EtOAc (3×15 mL), and the combined organicphase dried over MgSO₄, and concentrated to dryness. The residue ispurified by flash chromatography on silica gel (10% MeOH/CH₂Cl) to givethe pure cholic acid gabapentin dipeptide derivative. The correspondingsodium salt (9) is prepared in quantitative yield by addition of amethanol solution of the acid to water containing 0.5N NaOH (1 eq.) andevaporation to dryness on a lyophilizer.

Example 2 Synthesis of Cholic Acid Pregabalin Dipeptides (12)

Pregabalin (3), prepared according the methods described in Silverman etal (U.S. Pat. No. 5,563,175), is transformed to the cholyl dipeptidederivative (12) following the procedure detailed above for thegabapentin analog (9).

Cholyl-Gly-Pregabalin (12a):

MS (ESI): m/z 605.57 (M−H⁻), 607.55 (M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 3.81 (s, 2H),1.03 (d, 3H, J=6.4 Hz), 0.91 (s, 3H), 0.83 (d, 3H, J=6.4 Hz), 0.81 (d,3H, J=6.4 Hz), 0.70 (s, 3H).

Cholyl-Gly-Pregabalin (12g):

MS (ESI): m/z 695.58 (M−H⁻), 697.53 (M+H⁺).

¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 7.25 (m, 5H),4.60 (m, 1H), 3.25-2.95 (m, 2H), 1.03 (d, 3H, J=6.4 Hz), 0.91 (s, 3H),0.83 (d, 3H, J=6.4 Hz), 0.81 (d, 3H, J=6.4 Hz), 0.70 (s, 3H).

Example 3 In Vitro Compound Transport Assays with IBAT andLBAT-Expressing Cell Lines

(a) Inhibition of Radiolabeled Taurocholate Uptake

CHO cells transfected with the IBAT or LBAT transporter were seeded into96-well microtiter plates at 100,000 cells/well in 100 μL DMEMcontaining 10% serum, glutamine and Penstrep. After overnight incubationthe media was removed and test compound (25 μL) added at 2× the finaldesired concentration. Tritiated taurocholate (50,000 CPM/well) wasdiluted with cold substrate to a final concentration of 5 μM and 25μL/well of this mixture was added to the plate. After incubating for 1 hat room temperature the solution was removed and the plate washed 4×with PBS at 4° C. 200 μL/well of scintillant is added and the plate thenread in a Wallac microbeta counter. The inhibition data is processed bystandard methods to calculate an inhibition constant K_(i) for the testcompound.

(b) Analysis of Electrogenic Transport in Xenopus Oocytes

RNA preparation: Human IBAT Transporter cDNAs were subcloned into amodified pGEM plasmid that contains 5′ and 3′ untranslated sequencesfrom the Xenopus β-actin gene. These sequences increase RNA stabilityand protein expression. Plasmid cDNA was linearized and used as templatefor in vitro transcription (Epicentre Technologies transcription kit,4:1 methylated:non-methylated GTP).

Xenopus oocyte isolation. Xenopus laevis frogs were anesthetized byimmersion in Tricaine (1.5 g/mL in deionized water) for 15 min. Oocyteswere removed and digested in frog ringer solution (90 mM NaCl, 2 mM KCl,1 mM MgCl₂, 10 mM NaHEPES, pH 7.45, no CaCl₂) with 1 mg/mL collagenase(Worthington Type 3) for 80-100 min with shaking. The oocytes werewashed 6 times, and the buffer changed to frog ringer solutioncontaining CaCl₂ (1.8 mM). Remaining follicle cells were removed ifnecessary. Cells were incubated at 16° C., and each oocyte injected with10-20 μg RNA in 45 μL solution.

Electrophysiology measurements. Transport currents were measured 2-14days after injection, using a standard two-electrode electrophysiologyset-up (Geneclamp 500 amplifier, Digidata 1320/PCLAMP software andADInstruments hardware and software were used for signal acquisition).Electrodes (24 mΩ) were microfabricated using a Sutter Instrument pullerand filled with 3M KCl. The bath was directly grounded (transportercurrents were less than 0.3 μA). Bath flow was controlled by anautomated perfusion system (ALA Scientific Instruments, solenoidvalves).

For transporter pharmacology, oocytes were clamped at −60 to −90 mV, andcontinuous current measurements acquired using PowerLab Software and anADInstruments digitizer. Current signals were lowpass filtered at 20 Hzand acquired at 4-8 Hz. All bath and drug-containing solutions were frogringers solution containing CaCl₂. Drugs were applied for 10-30 secondsuntil the induced current reached a new steady-state level, followed bya control solution until baseline currents returned to levels thatpreceded drug application. The difference current (baseline subtractedfrom peak current during drug application) reflected the net movement ofcharge resulting from electrogenic transport and was directlyproportional to tranport rate. Recordings were made from a single oocytefor up to 60 min, enabling 30-40 separate compounds to be tested peroocyte. Compound-induced currents were saturable and gave half-maximalvalues at substrate concentrations comparable to radiolabel competitionexperiments. To compare results between oocytes expressing differentlevels of transport activity, a saturating concentration ofglycodeoxycholate (300 μM) was used as a common reference to normalizeresults from test compounds. Using this normalization procedure V_(max)(i.e. maximal induced current) for different compounds tested ondifferent oocytes could be compared. TABLE 1 In vitro transport data forselected compounds on IBAT-expressing cells IC₅₀ COMPOUND (μM) EC₅₀ (μM)% Max. (GDC) Cholyl-Gly-Gabapentin (9a) 66 22 67 Cholyl-Phe-Gabapentin(9g) 92 140 28 Cholyl-Tyr-Gabapentin (9h) 52 160 13 UDC-Phe-Gabapentin(9p) 27 18 27IC₅₀ data from radiolabeled competition assay in transporter-expressingCHO cellsEC₅₀ and % Max data (relative to glycodeoxycholate) fromtransporter-expressing oocytes

TABLE 2 In vitro transport data for selected compounds onLBAT-expressing cells COMPOUND IC₅₀ (μM) EC₅₀ (μM) % Max. (GDC)Cholyl-Gly-Gabapentin (9a) 64 ND ND Cholyl-Phe-Gabapentin (9g) 0.5 ND NDCholyl-Tyr-Gabapentin (9h) 15 ND ND UDC-Phe-Gabapentin (9p) 0.7 ND NDIC₅₀ data from radiolabeled competition assay in transporter-expressingCHO cellsEC₅₀ and % Max data (relative to glycodeoxycholate) fromtransporter-expressing oocytes

Example 4 In Vitro Compound Transport Assays with PEPT1 andPEPT2-Expressing Cell Lines—Inhibition of Radiolabeled Gly-Sar Uptake

Rat and human PEPT1 and PEPT2 expressing CHO cell lines were prepared asdescribed in PCT Application WO01/20331. Gabapentin-containingdipeptides were evaluated for interaction with the peptide transportersusing a radiolabeled substrate uptake assay in a competitive inhibitionformat, as described in PCT Application WO01/20331. Transport-inducedcurrents were also measured in Xenopus oocytes transfected with rat andhuman PEPT1 and PEPT2. TABLE 3 In vitro transport data for selectedcompounds on rPEPT1-expressing cells IC₅₀ COMPOUND (μM) % Max. (Gly-Sar)Gly-Gabapentin 320 76 Phe-Gabapentin 56 52 Tyr-Gabapentin 130 22IC₅₀ data from radiolabeled competition assay in transporter-expressingCHO cells% Max response (relative to Gly-Sar) from transporter-expressing oocytesat a test compound concentration of 1 mM

TABLE 4 In vitro transport data for selected compounds onrPEPT2-expressing cells IC₅₀ COMPOUND (μM) % Max. (Gly-Sar)Gly-Gabapentin ND ND Phe-Gabapentin ND 77 Tyr-Gabapentin 4 73IC₅₀ data from radiolabeled competition assay in transporter-expressingCHO cells% Max response (relative to Gly-Sar) from transporter-expressing oocytesat a test compound concentration of 1 mM

Example 5 In Vitro Enzymatic Release of Gabapentin from Cholyl-AminoAcid-Gabapentin Conjugates

Sustained oral delivery of a drug molecule by attachment through acleavable linker arm to an actively transported promoiety requires thatthe drug eventually be released from the drug/cleavablelinker/transporter compound (prodrug) by enzymatic cleavage in one ormore tissues of the enterohepatic circulation. The release of Gabapentinfrom the prodrug Cholyl-Phe-Gabapentin (9g) (and other Cholyl-AminoAcid-Gabapentin conjugates (9)) was evaluated in vitro using tissuesrepresentative of those involved in the enterohepatic circulation. Thesestudies indicated that in vitro cleavage of the prodrug could occur viaa stepwise process, with release of the Gabapentin-containing dipeptide(e.g. Phe-Gabapentin) preceeding hydrolysis to liberate free Gabapentin.

Tissues were obtained from commercial sources (e.g., Pel-FreezBiologicals, Rogers, Ark., or GenTest Corporation, Woburn, Mass.).Stability of Cholyl-Phe-Gabapentin towards specific enzymes (e.g.,carboxypeptidase A, cholylglycine hydrolase) was also evaluated byincubation with the purified enzyme.

Experimental conditions used for the in vitro studies are described inTable 3 below. Each preparation was incubated with (9g) at 37° C. forone hour. Aliquots (50 μL) were removed at 0, 30, and 60 min andquenched with 0.1% trifluoroacetic acid in acetonitrile. Samples werethen centrifuged and analyzed by LC/MS/MS as described below.

The stability of Gabapentin-containing dipeptides to purifiedaminopeptidase 1 and to Caco-2 homogenates was evaluated as follows:

Aminopeptidase Stability: Aminopeptidase 1 (Sigma catalog # A-9934) wasdiluted in deionised water to a concentration of 856 units/mL. Stabilitystudies were conducted by incubating prodrug (5 μM) with 0.856 units/mLaminopeptidase 1 in 50 mM Tris-HCl buffer at pH 8.0 and 37° C.Concentrations of intact prodrug and released drug were determined atzero time and 60 minutes using LC/MS/MS.

Pancreatin Stability: Stability studies were conducted by incubatingprodrug (5 μM) with 1% (w/v) pancreatin (Sigma, P-1625, from porcinepancreas) in 0.025 M Tris buffer containing 0.5 M NaCl (pH 7.5) at 37°C. for 60 min. The reaction was stopped by addition of 2 volumes ofmethanol. After centrifugation at 14,000 rpm for 10 min, the supernatantwas removed and analyzed by LC/MS/MS.

Caco-2 Homogenate S9 Stability: Caco-2 cells were grown for 21 daysprior to harvesting. Culture medium was removed and cell monolayers wererinsed and scraped off into ice-cold 10 mM sodium phosphate/0.15 Mpotassium chloride, pH 7.4. Cells were lysed by sonication at 4° C.using a probe sonicator. Lysed cells were then transferred into 1.5 mLcentrifuge vials and centrifuged at 9000 g for 20 min at 4° C. Theresulting supernatant (Caco-2 cell homogenate S9 fraction) was aliquotedinto 0.5 mL vials and stored at −80° C. until used. For stabilitystudies, prodrug (5 μM) was incubated in Caco-2 homogenate S9 fraction(0.5 mg protein per mL) for 60 min at 37° C. Concentrations of intactprodrug and released drug were determined at zero time and 60 minutesusing LC/MS/MS.

Concentrations of Cholyl-Phe-Gabapentin (9g), Phe-Gabapentin orGabapentin in tissue extracts were determined by direct injection ontoan API 2000 LC/MS/MS equipped with an Agilent 1100 binary pump andautosampler. Separation was achieved using a 3.5 μm Zorbax EllipseXDB-C8 4.4×150 mm column heated to 45° C. during the analysis. Themobile phases were: 0.1% formic acid in water (A) and 0.1% formic acidin acetonitrile (B). The gradient condition was: 2% B for 0.5 min,increasing to 90% B in 2.0 min, maintained for 2.5 min and returning to2% B for 2 min. A TurboIonSpray source was used on the API 2000. Theanalysis was performed in the positive ion mode and MRM transitions of709.5/172.1 and 172.0/137.2 were used in the analysis ofCholyl-Phe-Gabapentin (9g) and Gabapentin (2) respectively. Tenmicroliters of the sample extracts were injected. Peaks were integratedusing Analyst quantitation software. The method was linear for (9g) or(2) over the concentration range 0.01 to 12.5 μg/mL and 0.002 to 2.5μg/mL respectively. TABLE 5 In Vitro Enzymatic Release of Phe-Gabapentinfrom Cholyl-Phe-Gabapentin (9g) Percent of Phe- Substrate GabapentinPreparation Concentration Cofactors Released in 60 min Rat Plasma 2.0 μMNone NR Human Plasma 2.0 μM None NR Rat Liver S9 2.0 μM NADPH NR (0.5mg/mL) Human Liver S9 2.0 μM NADPH NR (0.5 mg/mL) Human Intestine 2.0 μMNADPH NR S9 (0.5 mg/mL) Cholylglycine 0.8 μM None ˜3 Hydrolase (87units/mL) Carboxypeptidase A 2.0 μM None NR (10 units/mL)NR = Not released

TABLE 6 In Vitro Enzymatic Release of Gabapentin (2) from Phe-GabapentinPercent of Substrate Gabapentin Preparation Concentration CofactorsReleased in 60 min Rat Plasma 2.0 μM None 19 Human Plasma 2.0 μM None NRRat Liver S9 2.0 μM NADPH  1 (0.5 mg/mL) Human Liver S9 2.0 μM NADPH  1(0.5 mg/mL) Human Intestine 2.0 μM NADPH  5 S9 (0.5 mg/mL) Cholylglycine0.8 μM None NR Hydrolase (87 units/mL) Carboxypeptidase A 2.0 μM None NR(10 units/mL) Caco-2 5.0 μM None 21 Homogenate Aminopeptidase 5.0 μMNone 24NR = Not released

TABLE 7 In Vitro Enzymatic Release of Gabapentin (2) from Cholyl-AminoAcid-Gabapentin Compounds by Pancreatin COMPOUND % (2) ReleasedCholyl-Gly-Gabapentin (9a) NR Cholyl-Phe-Gabapentin (9g)  4Cholyl-Tyr-Gabapentin (9h) 40NR = Not released

Example 6

Sustained Release of Gabapentin (2) from Cholyl-Phe-Gabapentin (9g)Following Oral Administration to Rats

The pharmacokinetics of the prodrug Cholyl-Phe-Gabapentin (9g) wereexamined in rats. Three groups of four male Sprague-Dawley rats (approx200 g) with jugular cannulae each received one of the followingtreatments: A) a single bolus intravenous injection of Gabapentin (25mg/kg, as a solution in water); B) a single oral dose of Gabapentin (25mg/kg, as a solution in water) administered by oral gavage; C) a singleoral dose of (9g) (103.5 mg/kg, as a solution in water) administered byoral gavage. Animals were fasted overnight prior to dosing and until 4hours post-dosing. Serial blood samples were obtained over 24 hoursfollowing dosing and blood was processed for plasma by centrifugation.Plasma samples were stored at −80° C. until analyzed.

Concentrations of (9g) or (2) in plasma samples were determined byLC/MS/MS as described above. Plasma (50 μL) was precipitated by additionof 100 mL of methanol and supernatent was injected directly onto theLC/MS/MS system. Following oral administration of Gabapentin,concentrations of Gabapentin in plasma reached a maximum at 1.3±0.5hours (T_(max)) and declined thereafter with a terminal half-life of3.0±1.3 hours. The oral bioavailability of Gabapentin was 87±18%.Following oral administration of Cholyl-Phe-Gabapentin (9g),concentrations of Gabapentin in plasma reached a maximum at ˜7.1 hourspost-dosing and declined thereafter with a terminal half-life of ˜5.1hours. Concentrations of released Gabapentin in plasma were sustainedbeyond 24 hours. These data indicate that prodrug Cholyl-Phe-Gabapentin(9g) is metabolized to Gabapentin (2) in vivo, and that a substantiallysustained release of Gabapentin was achieved following oraladministration of (9g) compared to the relatively rapid clearanceobserved for oral Gabapentin.

Example 7 Sustained Release of Gabapentin (2) from Cholyl-Gly-Gabapentin(9a) Following Oral Administration to Rats

Following oral administration of Cholyl-Gly-Gabapentin (9a) (90.4 mg/kg,as a solution in water) according to the protocol of Example 6 above,concentrations of Gabapentin in plasma reached a maximum at ˜8.0 hourspost-dosing and declined thereafter with a terminal half-life of ˜6.9hours. Concentrations of released Gabapentin in plasma were sustainedbeyond 24 hours. These data indicate that prodrug Cholyl-Gly-Gabapentin(9a) is metabolized to Gabapentin (2) in vivo, and that a substantiallysustained release of Gabapentin was achieved following oraladministration of (9a) compared to the relatively rapid clearanceobserved for oral Gabapentin.

Example 8 Sustained Release of Gabapentin (2) from Cholyl-Tyr-Gabapentin(9h) Following Oral Administration to Rats

Following oral administration of Cholyl-Tyr-Gabapentin (9h) (106 mg/kg,as a solution in water) according to the protocol of Example 6 above,concentrations of Gabapentin in plasma reached a maximum at ˜7.3 hourspost-dosing and declined thereafter with a terminal half-life of ˜4.5hours.

Concentrations of released Gabapentin in plasma were sustained beyond 24hours. These data indicate that prodrug Cholyl-Tyr-Gabapentin (9h) ismetabolized to Gabapentin (2) in vivo, and that a substantiallysustained release of Gabapentin was achieved following oraladministration of (9h) compared to the relatively rapid clearanceobserved for oral Gabapentin.

In view of the above disclosure, it is understood, of course, thatcombinations of substituents within the compounds of the presentinvention do not include any combination that is chemically impossibleor non-feasible as would be appreciated by one skilled in the art.

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Each of the above references is incorporated herein by reference in itsentirety.

1. A compound of formula (I):

wherein: R¹ and R² are independently hydrogen or hydroxy; X is Q^(x)-G-where: G is —O—, —C(O)O— or —NH—; Q^(x) is a group derived from a linearoligopeptide comprising a first moiety D and further comprising from 1to 3 amino acids, and wherein said group is cleavable from (I) underphysiological conditions; D is a GABA analog moiety; Z is a substitutedalkyl group containing a moiety which is negatively charged atphysiological pH, which moiety is selected from the group consisting of—COOH, —SO₃H, —SO₂H, —P(O)(OR¹⁶)(OH), —OP(O)(OR¹⁶)(OH), —OSO₃H and thelike, and where R¹⁶ is selected from the group consisting of alkyl,substituted alkyl, aryl and substituted aryl; or a pharmaceuticallyacceptable salt thereof.
 2. The compound according to claim 1 whereinQ^(x) is transported by a transporter selected from a group consistingof PEPT1 oligopeptide transporter and PEPT2 oligopeptide transporter. 3.(canceled)
 4. The compound according to claim 1 wherein Q^(x) is of oneof the following two structures:—I_(i)-J_(j)-D-K_(k)—R⁴⁰or-T_(t)-D-U_(u)—V_(v)—R⁴¹ wherein I is—[NR⁵⁰—(CR⁵¹R⁵²)_(a)—(CR⁵³R⁵⁴)_(b)—C(O)]—; J is—[NR⁵⁵—(CR⁵⁶R⁵⁷)_(c)—(CR⁵⁸R⁵⁹)_(d)—C(O)]—; K is—[NR⁶⁰—(CR⁶¹R⁶²)_(e)—(CR⁶³R⁶⁴)_(f)—C(O)]—; T is—[C(O)—(CR⁶⁵R⁶⁶)_(g)—(CR⁶⁷R⁶⁸)_(h)—NR⁶⁹]—; U is—[C(O)—(CR⁷⁰R⁷¹)_(m)—(CR⁷²R⁷³)_(n)—NR⁷⁴]—; V is—[C(O)—(CR⁷⁵R⁷⁶)_(o)—(CR⁷⁷R⁷⁸)_(p)—NR⁷⁹]—; R⁴⁰ is —OH or —OR¹⁷; R⁴¹ isH, —C(O)R¹⁷, or —C(O)OR¹⁷; R¹⁷ is alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, or substituted heteroaryl; a, b, c, d, e,f, g, h, m, n, o and p are independently 0 or 1, wherein at least one ofa and b is 1; at least one of c and d is 1; at least one of e and f is1; at least one of g and h is 1; at least one of m and n is 1; at leastone of o and p is 1; i, j, k, t, u and v are independently 0 or 1; R⁵⁰is hydrogen or R⁵⁰ and R⁵¹ together with the atoms to which they areattached form a heterocyclyl ring; R⁵¹ is hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁵¹ and R⁵² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or R⁵¹ and R⁵³ together with the atoms to which theyare attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl orsubstituted heterocyclyl ring; R⁵² is hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴together with the atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁵⁵ is hydrogen or R⁵⁵ and R⁵⁶,together with the atoms to which they are attached form a heterocyclylring; R⁵⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵⁶ and R⁵⁷ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵⁶ andR⁵⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁵⁷ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁵⁸ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁵⁸ and R⁵⁹ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R⁵⁹ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁶⁰ is hydrogen or R⁶⁰ and R⁶¹, together with the atoms towhich they are attached form a heterocyclyl ring; R⁶¹ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁶¹ and R⁶² together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring, or R⁶¹ and R⁶³ togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R⁶² ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁶³ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁶³ and R⁶⁴ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁶⁴ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁶⁵ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁶⁵ and R⁶⁶ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring, or R⁶⁵ and R⁶⁷ togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R⁶⁶ ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁶⁷ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁶⁷ and R⁶⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁶⁸ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁶⁹ is hydrogenor R⁶⁹ and R⁶⁸ together with the atoms to which they are attached form aheterocyclyl ring; R⁷⁰ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R⁷⁰ and R⁷¹together with the atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring,or R⁷⁰ and R⁷² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁷¹ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁷² is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁷² and R⁷³ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R⁷³ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁷⁴ is hydrogen or R⁷⁴ and R⁷³ together with the atoms towhich they are attached form a heterocyclyl ring; R⁷⁵ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁷⁵ and R⁷⁶ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring, or R⁷⁵ and R⁷⁷ togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R⁷⁶ ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁷⁷ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁷⁷ and R⁷⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁷⁸ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; and R⁷⁹ ishydrogen or R⁷⁹ and R⁷⁸ together with the atoms to which they areattached form a heterocyclyl ring.
 5. (canceled)
 6. The compoundaccording to claim 1, wherein R¹ and R² are both α-OH; or R¹ is β-OH andR² is hydrogen; or R¹ is α-OH and R² is hydrogen; or R¹ is hydrogen andR² is α-OH; or R¹ is α-OH and R² is α-OH; or R¹ and R² are bothhydrogen.
 7. The compound according to claim 1, wherein D is a moietyderived from a GABA analog having the following formula:

wherein R³ is a covalent bond linking D to either J_(j) or U_(u); R⁴ ishydrogen, or R⁴ and R⁹ together with the atoms to which they areattached form a heterocyclic ring; R⁵ and R⁶ are independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, aryl, substituted aryl,heteroaryl and substituted heteroaryl; R⁷ and R⁸ are independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl, or R⁷ and R⁸ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclic or substituted heterocyclic ring; R⁹ is selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl; R¹¹ is —C(O)R¹²; R¹² is a covalent bondlinking D to either K_(k) or T_(t); or a pharmaceutically acceptablesalt thereof.
 8. (canceled)
 9. The compound according to claim 3,wherein I, J, K, T, U and V are moieties derived from naturallyoccurring α-amino acids.
 10. (canceled)
 11. The compound according toclaim 6, wherein D is a moiety derived from a GABA analog, which moietyis selected from the group consisting of:


12. (canceled)
 13. The compound according to claim 7, wherein b, c, d,e, f, g, h, j, k, m, n, o and p are 0, and wherein a and i are 1.14.-21. (canceled)
 22. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound according to claim 1.23. A method for achieving sustained therapeutic or prophylactic bloodconcentrations of a drug or an active metabolite thereof in the systemiccirculation of an animal which method comprises administering to theanimal a compound according to claim
 1. 24. A composition according toclaim 1 for treating or preventing epilepsy in a patient in need of suchtreatment or prevention.
 25. A composition according to claim 9 fortreating or preventing neuropathological disorders in a patient in needof such treatment or prevention.
 26. A composition according to claim 9for treating or preventing depression in a patient in need of suchtreatment or prevention.
 27. A composition according to claim 9 fortreating or preventing anxiety in a patient in need of such treatment orprevention.
 28. A composition according to claim 9 for treating orpreventing psychosis in a patient in need of such treatment orprevention.
 29. A composition according to claim 9 for treating orpreventing faintness attacks in a patient in need of such treatment orprevention.
 30. A composition according to claim 9 for treating orpreventing hypokinesia in a patient in need of such treatment orprevention.
 31. A composition according to claim 9 for treating orpreventing cranial disorders in a patient in need of such treatment orprevention.
 32. A composition according to claim 9 for treating orpreventing nuerodegenerative disorders in a patient in need of suchtreatment or prevention.
 33. A composition according to claim 9 fortreating or preventing panic in a patient in need of such treatment orprevention.
 34. A composition according to claim 9 treating orpreventing pain in a patient in need of such treatment or prevention.35. A composition according to claim 9 for treating or preventingneuropathic pain in a patient in need of such treatment or prevention.36. A composition according to claim 9 for treating or preventingmuscular or skeletal pain in a patient in need of such treatment orprevention.
 37. A composition according to claim 9 for treating orpreventing inflammatory disease in a patient in need of such treatmentor prevention.
 38. A composition according to claim 9 for treating orpreventing gastrointestinal disorders in a patient in need of suchtreatment or prevention.
 39. A composition according to claim 9 fortreating or preventing ethanol withdrawal syndrome in a patient in needof such treatment or prevention.
 40. A method for treating or preventingepilepsy in a patient comprising administering to a patient in need ofsuch treatment or prevention a therapeutically effective amount of acomposition according to claim
 1. 41. A method for treating orpreventing neuropathological disorders in a patient comprisingadministering to a patient in need of such treatment or prevention atherapeutically effective amount of a composition according to claim 1.42. A method for treating or preventing depression in a patientcomprising administering to a patient in need of such treatment orprevention a therapeutically effective amount of a composition accordingto claim
 1. 43. A method for treating or preventing anxiety in a patientcomprising administering to a patient in need of such treatment orprevention a therapeutically effective amount of a composition accordingto claim
 1. 44. A method for treating or preventing psychosis in apatient comprising administering to a patient in need of such treatmentor prevention a therapeutically effective amount of a compositionaccording to claim
 1. 45. A method for treating or preventing faintnessattacks in a patient comprising administering to a patient in need ofsuch treatment or prevention a therapeutically effective amount of acomposition according to claim
 1. 46. A method for treating orpreventing hypokinesia in a patient comprising administering to apatient in need of such treatment or prevention a therapeuticallyeffective amount of a composition according to claim
 1. 47. A method fortreating or preventing cranial disorders in a patient comprisingadministering to a patient in need of such treatment or prevention atherapeutically effective amount of a compound according to claim
 1. 48.A method for treating or preventing neurodegenerative disorders in apatient comprising administering to a patient in need of such treatmentor prevention a therapeutically effective amount of a compositionaccording to claim
 1. 49. A method for treating or preventing panic in apatient comprising administering to a patient in need of such treatmentor prevention a therapeutically effective amount of a compositionaccording to claim
 1. 50. A method for treating or preventing pain in apatient comprising administering to a patient in need of such treatmentor prevention a therapeutically effective amount of a compositionaccording to claim
 1. 51. A method for treating or preventingneuropathic pain in a patient comprising administering to a patient inneed of such treatment or prevention a therapeutically effective amountof a composition according to claim
 1. 52. A method for treating orpreventing muscular and skeletal pain in a patient comprisingadministering to a patient in need of such treatment or prevention atherapeutically effective amount of a composition according to claim 1.53. A method for treating or preventing inflammatory diseases in apatient comprising administering to a patient in need of such treatmentor prevention a therapeutically effective amount of a compositionaccording to claim
 1. 54. A method for treating or preventinggastrointestinal disorders in a patient comprising administering to apatient in need of such treatment or prevention a therapeuticallyeffective amount of a composition according to claim
 1. 55. A method fortreating or preventing ethanol withdrawal syndrome in a patientcomprising administering to a patient in need of such treatment orprevention a therapeutically effective amount of a composition accordingto claim 1.